Benzoxazine and benzothiazine derivatives and the use thereof in medicaments

ABSTRACT

The invention relates to compounds of formula (I), the tautomeric and isomeric forms and salts thereof, in addition to a method for production and use thereof in medicaments.

The invention relates to benzoxazine and benzothiazine derivatives, theprocess for their production and their use in pharmaceutical agents.

In human cells, there exist at least three forms of nitrogen monoxidesynthases, which convert arginine into nitrogen monoxide (NO) andcitrulline. Two constitutive NO-synthases (NOS) were identified that arepresent as calcium/calmodulin-dependent enzymes in the brain (ncNOS orNOS 1) or in the endothelium (ecNOS or NOS 3). Another isoform is theinducible NOS (iNOS or NOS 2), which is a virtually Ca⁺⁺-independentenzyme and is induced after activation of different cells by endotoxinor other substances.

NOS-inhibitors and especially selective inhibitors of NOS 1, NOS 2 orNOS 3 are therefore suitable for treatment of different diseases, whichare induced or aggravated by pathological concentrations of NO in cells.A number of reviews provide information on the action and inhibitors ofNO-synthases. Mentioned are, for example: Drugs 1998, 1, 321 or CurrentPharmac. Design 1997, 3, 447.

As NOS-inhibitors, different compounds are known. For example, argininederivatives, aminopyridines, cyclic amidine derivatives,phenylimidazoles, etc., are described. It is known from WO 98/50372 that3-amino-2H-1,4-benzoxazines or 3-amino-2H-1,4-benzothiazines inhibitnitrogen monoxide synthases in a potent and selective manner.

It has now been found that the heterocyclic compounds that aresubstituted according to the invention, compared to known compounds,have advantages and can be better used as pharmaceutical agents.

The invention relates to the compounds of formula I, their tautomericand isomeric forms and salts

in which

-   -   X means O, SO_(m)    -   R¹ means —(CHR⁹)_(n)—NR⁷—A—NR⁸—B,        —(CHR⁹)_(n)—NR⁷—(CH₂)_(p)—C═R—(CH₂)_(q)— NR⁸—D or        —(CHR⁹)_(n)—NR⁷—B,    -   R² means hydrogen or    -   R¹ and R² together with two adjacent carbon atoms form a 5-, 6-,        7- or 8-membered ring, which is monocyclic or bicyclic,        saturated or unsaturated and in which 1 or 2 CH₂ groups can be        replaced by oxygen or carbonyl, and which is substituted with        (CHR⁹)_(r)—NR⁷—A—NR⁸—B,        —(CHR⁹)_(r)—NR⁷—(CH₂)_(p)—C═R—(CH₂)_(q)—NR⁸—D or        —(CHR⁹)_(r)—NR⁷—B and can be substituted with C₁₋₄ alkyl,    -   R³ means hydrogen, halogen, NO₂, cyano, CF₃, —OCF₃, —S—R⁹,        —O—R⁹, C₃₋₇ cycloalkyl, —NR⁹—C(═NR¹⁰)—R¹¹, —NH—CS—NR¹²R¹³,        NH—CO—NR¹²R¹³, —SO₂NR¹²R¹³, —CO—NR¹²R¹³, —CO—R⁴, NR¹⁵R⁶, C₆₋₁₀        aryl, which optionally is substituted with halogen, cyano, C₁₋₄        alkyl, —S—R⁹, or —O—R⁹,        -   5- or 6-membered heteroaryl with 1 to 4 oxygen, sulfur or            nitrogen atoms,        -   C₁₋₆ alkyl, which optionally is substituted with halogen,            —OR⁹, —SR⁹, —NR¹²R¹³, ═NR¹², ═NOC₁₋₆ alkyl, ═N—NHaryl,            phenyl, C₃₋₇ cycloalkyl or 5- or 6-membered heteroaryl,        -   C₂₋₆ alkenyl, which optionally is substituted with halogen,            CONH₂, C≡N or phenyl,        -   C₂₋₆ alkinyl, which optionally is substituted with halogen,            CONH₂, C≡N or phenyl,    -   R⁴ means hydrogen or acyl,    -   R⁵ and R⁶, independently of one another, mean hydrogen, C₃₋₇        cycloalkyl, phenyl, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl        radicals, which can be substituted in each case with halogen,        OH, O—C₁₋₆ alkyl, SH, S—C₁₋₆ alkyl, NR¹⁵R¹⁶, 5- or 6-membered        heteroaryl with 1–3 N, O or S atoms, phenyl or C₃₋₇ cycloalkyl,    -   R⁷ means hydrogen, C₁₋₆ alkyl, which can be substituted with        phenyl, COOC₁₋₆ alkyl or COC₁₋₆ alkyl,    -   R⁸ means hydrogen,    -   A means straight-chain or branched C₁₋₆ alkylene, straight-chain        or branched C₂₋₆ alkenylene or —(CH₂)_(p)—Q—(CH₂)_(q)—,    -   B means —C═R—(CH₂)_(p)—U, —C═R—NR¹⁵R¹⁶, —SOR¹², —SOR¹²,        —C═O—O-aryl or —C═O—O-benzyl,    -   D means hydrogen or —(CH₂)_(p)—U,    -   R means oxygen or sulfur,    -   Q means C₃₋₇ cycloalkyl, indanyl, 5-, 6- or 7-membered saturated        heterocycloalkyl with 1–2 N, O or S atoms, C₆–C₁₀ aryl or 5- or        6-membered heteroaryl with 1–3 N, O or S atoms, which can be        anellated with benzene,    -   U means hydrogen, C₁₋₆ alkyl optionally substituted with        halogen, C₃₋₇ cycloalkyl, indanyl, C₇₋₁₀ bicycloalkyl, C₆₋₁₀        aryl or 5- or 6-membered heteroaryl with 1–3 N, O or S atoms,        which can be anellated with benzene, whereby the aryl and        heteroaryl radical can be substituted with halogen, C₁₋₄ alkyl,        C₁₋₄ alkoxy, CF₃, NO₂, NH₂, N(C₁₋₄ alkyl)₂, cyano, CONH₂,        —O—CH₂—O—, —O—(CH₂)₂—O—, SO₂NH₂, OH, phenoxy or COOC₁₋₄ alkyl,        or    -   R⁸ and B together with the nitrogen atom form a 5- to 7-membered        saturated heterocyclic compound, which contains a carbonyl or        thiocarbonyl group and optionally can contain another oxygen,        nitrogen or sulfur atom and can be substituted with C₁₋₄ alkyl        or a phenyl, benzyl or benzoyl radical that is optionally        substituted with halogen, or    -   R⁷ and A together with the nitrogen atom form a 5- to 7-membered        saturated heterocyclic compound, which can contain another        oxygen, nitrogen or sulfur atom or forms an unsaturated        5-membered heterocyclic compound, which can contain 1 to 3 N        atoms,    -   m means 0, 1 or 2,    -   n and r mean 0, 1 to 6,    -   p and q mean 0 to 6,    -   R⁹ and R¹⁰ mean hydrogen or C₁₋₆ alkyl,    -   R¹¹ means C₁₋₆ alkyl, —NH₂, —NH—CH₃, —NH—CN, C₆₋₁₀ aryl        optionally substituted with halogen, C₁₋₄ alkyl or CF₃, or 5- or        6-membered heteroaryl with 1 to 4 nitrogen, sulfur or oxygen        atoms that is optionally substituted with halogen, C₁₋₄ alkyl or        CF₃,    -   R¹² and R¹³ mean hydrogen, C₁₋₆ alkyl, phenyl optionally        substituted with halogen or C₁₋₄ alkyl, benzyl optionally        substituted with halogen or C₁₋₄ alkyl, or C₃₋₇ cycloalkyl,    -   R¹⁴ means hydrogen, hydroxy, C₁₋₆ alkoxy, phenyl, C₁₋₆ alkyl        optionally substituted with CO₂H, CO₂C₁₋₆ alkyl, hydroxy, C₁₋₄        alkoxy, halogen, NR¹⁵R₁, CONR¹²R¹³, or phenyl, or C₂₋₆ alkenyl        optionally substituted with phenyl, cyano, CONR¹²R¹³ or CO₂C₁₋₄        alkyl,    -   R¹⁵ and R¹⁶ mean hydrogen, C₁₋₆ alkyl, phenyl optionally        substituted with halogen or C₁₋₄ alkyl, or benzyl optionally        substituted with halogen or C₁₋₄ alkyl,    -   R¹⁵ and R¹⁶ together with the nitrogen atom form a saturated 5-,        6-, or 7-membered ring, which can contain another nitrogen,        oxygen or sulfur atom and can be substituted with C₁₋₄ alkyl, or        a phenyl, benzyl or benzoyl radical optionally substituted with        halogen.

The compounds of formula I can be present as tautomers, stereoisomers orgeometric isomers. The invention also comprises all possible isomers,such as E- and Z-isomers, S- and R-enantiomers, diastereomers, racematesand mixtures thereof, including the tautomeric compounds of Formulas Iaand Ib

The physiologically compatible salts can be formed with inorganic andorganic acids, such as, for example, oxalic acid, lactic acid, citricacid, fumaric acid, acetic acid, maleic acid, tartaric acid, phosphoricacid, HCl, HBr, sulfuric acid, p-toluenesulfonic acid, methanesulfonicacid, i.a.

For salt formation of acid groups, the inorganic or organic bases arealso suitable, which are known for the formation of physiologicallycompatible salts, such as, for example, alkali hydroxides, such assodium and potassium hydroxide, alkaline-earth hydroxides, such ascalcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine,triethanolamine, N-methylglucamine, tris-(hydroxymethyl)-methylamine,etc.

In each case, alkyl means a straight-chain or branched alkyl group, suchas, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, n-pentyl, sec-pentyl, tert-pentyl, neopentyl, n-hexyl,sec-hexyl, heptyl, or octyl.

If alkyl radical U is substituted with halogen, it can be halogenated inone or more places, in particular perhalogenated, such as CF₃, C₂F₅,CH₂F, 2-fluoroethyl.

Alkenyl and alkynyl substituents are in each case straight-chain orbranched. For example, the following radicals can be mentioned: vinyl,2-propenyl, 1-propenyl, 2-butenyl, 1-butenyl, 3-butenyl,2-methyl-2-propenyl, ethinyl, 1-propinyl, 2-propinyl, 1-butinyl,2-butinyl, 2-pentenyl, 4-hexenyl.

Cycloalkyl is defined respectively as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl. As a bicyclic compound, forexample, bicycloheptane and bicyclooctane can be mentioned.

Halogen means respectively fluorine, chlorine, bromine or iodine.

Aryl is defined respectively as naphthyl or phenyl, which can besubstituted by the same or a different component in one to three places.

As heteroaryl radicals, which can be bonded via the heteroatom or acarbon atom, for example, the following 5- and 6-ring heteroaromaticcompounds can be mentioned:

Imidazole, indole, isooxazole, isothiazole, furan, oxadiazole, oxazole,pyrazine, pyridazine, pyrimidine, pyridine, pyrazole, pyrrole,tetrazole, thiazole, triazole, thiophene, thiadiazole, benzimidazole,benzofuran, benzoxazole, isoquinoline, quinoline. As a heteroarylradical, 2-C₁₋₆ alkyl-3-amino-2H-1,4-benzoxazine and2-C₁₋₆-alkyl-3-keto-2H-1,4-benzoxazine are also suitable.

In the case of a substitution of the heteroaryl radical, the latter canbe substituted by the same or a different component in one to threeplaces.

As a preferred embodiment of R¹¹ in the meaning of heteroaryl, thienylcan be considered.

Saturated heterocyclic compounds are defined in each case as, forexample, piperidine, pyrrolidine, morpholine, thiomorpholine,hexahydroazepine and piperazine. The heterocyclic compound can besubstituted by the same or a different component in one to three placeswith C₁₋₄ alkyl or a phenyl, benzyl or benzoyl radical that isoptionally substituted with halogen. For example, there can bementioned: N-methyl-piperazine, 2,6-dimethylmorpholine, pyrrolidine,phenylpiperazine or 4-(4-fluorobenzoyl)-piperidine.

If —NR⁷A— together with the nitrogen atom forms an unsaturatedheterocyclic compound, for example, imidazole, pyrrole, pyrazole andtriazole can be mentioned.

Simple substitution is preferred for substituents R⁵ and R⁶ in2-position of the oxazine or thiazine, whereby substituent R⁵ inparticular means C₁₋₆ alkyl and R⁶ is hydrogen.

Substituent Q can be linked at any point via a C atom or optionally viaan N atom.

If R¹ and R² together with two adjacent carbon atoms form a ring, thelatter can be in 5,6- or 7,8- or especially 6,7-position of thebenzoxazine or benzothiazine and has the formula

in which

E means a saturated or unsaturated C₃₋₈ alkylene radical, which issubstituted in one to two places with —(CHR⁹)_(r)—NR⁷—A—NR⁸B,—(CHR⁹)_(r)—NR⁷— (CH₂)_(p)—C═R—(CH₂)_(q)—NR⁸—D or —(CHR⁹)_(r)—NR⁷—B andoptionally is substituted in one to two places with C₁₋₄ alkyl and inwhich 1 or 2 CH₂ groups can be replaced by oxygen, carbonyl or itsderivative, and whereby the alkylene radical can contain a slightlycondensed benzene radical, such as, for example, indan, or can bepresent as a bicyclic compound, such as, for example, bicycloheptane.

Substituent r stands in particular for zero.

As structures of E, there can be mentioned, for example:

As carbonyl derivatives, for example, ═NOH, ═N—OC₁₋₆ alkyl, ═NH—NH₂, and═N—NH-phenyl are suitable.

Preferably, two adjacent carbon atoms of the aromatic compound arelinked with C₃₋₆ alkylene, especially C₃₋₄ alkylene, to a 5- to8-membered ring E, especially to a 5- to 6-membered ring.

Acyl radical R⁴ is derived from straight-chain or branched aliphaticC₁₋₆ carboxylic acids, such as, for example, formic acid, acetic acid,propionic acid, butyric acid, trimethylacetic acid or caproic acid orfrom known benzenesulfonic acids, which can be substituted with halogenor C₁₋₄ alkyl, and C₁₋₄ alkanesulfonic acids, such as, for example,methanesulfonic acid, and p-toluenesulfonic acid.

Substituent n preferably stands for 1–6, especially for 1.

Preferred embodiments of X are S and especially O.

Preferred embodiments of R³, R⁴, R⁷ and R⁹ are in each case hydrogen.

Substituent R¹ is preferably in 6-position.

Ring E is preferably substituted in one place, whereby the substituentis in 6-position.

A preferred embodiment of A is straight-chain or branched C₁₋₆ alkylene.

If R⁸ and B together with the nitrogen atom form a saturatedheterocyclic compound, in particular pyrrolidine-2-thione is meant.

Preferred embodiments of B are —C═R—(CH₂)_(p)—U, —C═R—NR¹⁵R¹⁶ and—SO₂R¹², in which R¹², especially C₁₋₆ alkyl, R¹⁵ and R¹⁶ mean inparticular hydrogen, C₁₋₆ alkyl or phenyl, and —(CH₂)_(p)—U inparticular means hydrogen, C₁₋₆ alkyl optionally substituted withhalogen, or phenyl optionally substituted with halogen, C₁₋₄ alkyl, C₁₋₄alkoxy or CF₃.

Preferred embodiments of D are hydrogen and —(CH₂)_(p)—U in the meaningof a benzyl radical that is optionally substituted with halogen, C₁₋₄alkoxy, CF₃ or C₁₋₄ alkyl.

p and q preferably do not mean 0 simultaneously but rather either p or qmeans an alkylene radical with 1–6 carbon atoms.

The invention also relates to the use of the compounds according to theinvention for the production of a pharmaceutical agent for treatingdiseases that are induced by the action of nitrogen monoxide atpathological concentrations. These include neurodegenerative diseases,inflammatory diseases, auto-immune diseases, and cardiovasculardiseases.

For example, there can be mentioned:

Cerebral ischemia, hypoxia and other neurodegenerative diseases, whichare brought into contact with inflammations, such as multiple sclerosis,amyotrophic lateral sclerosis and comparable sclerotic diseases,Parkinson's Disease, Huntington's Disease, Korksakoff's Disease,epilepsy, vomiting, sleep disorders, schizophrenia, depression, stress,pain, migraine, hypoglycemia, dementia, such as, e.g., Alzheimer'sDisease, HIV-dementia and presenile dementia.

They are also suitable for treating diseases of the cardiovascularsystem and for treating auto-immune and/or inflammatory diseases, suchas hypotension, ARDS (adult respiratory distress syndrome), sepsis orseptic shock, rheumatoid arthritis, osteoarthritis, insulin-dependentdiabetes mellitus (IDDM), inflammatory disease of the pelvis/intestine(bowel disease), meningitis, glomerulonephritis, acute and chronic liverdiseases, diseases by rejection (for example allogenic heart, kidney orliver transplants) or inflammatory skin diseases such as psoriasis, etc.

Based on their profile of action, the compounds according to theinvention are very well suited for inhibiting the neuronal NOS.

To use the compounds according to the invention as pharmaceuticalagents, the latter are brought into the form of a pharmaceuticalpreparation, which in addition to the active ingredient containsvehicles, adjuvants and/or additives that are suitable for enteral orparenteral administration. The administration can be done orally orsublingually as a solid in the form of capsules or tablets or as aliquid in the form of solutions, suspensions, elixirs, aerosols oremulsions or rectally in the form of suppositories or in the form ofinjection solutions that can optionally also be administeredsubcutaneously, intramuscularly or intravenously, or topically orintrathecally. As adjuvants for the desired pharmaceutical agentformulation, the inert organic and inorganic support media that areknown to one skilled in the art are suitable, such as, e.g., water,gelatin, gum arabic, lactose, starch, magnesium stearate, talc, plantoils, polyalkylene glycols, etc. Moreover, preservatives, stabilizers,wetting agents, emulsifiers or salts for changing the osmotic pressureor buffers can optionally be contained.

For parenteral administration, especially injection solutions orsuspensions, especially aqueous solutions of the active compounds inpolyhydroxyethoxylated castor oil, are suitable.

As vehicle systems, surface-active adjuvants such as salts of bile acidsor animal or plant phospholipids, but also mixtures thereof as well asliposomes or their components can also be used.

For oral administration, especially tablets, coated tablets or capsuleswith talc and/or hydrocarbon vehicles or binders, such as, for example,lactose, corn or potato starch, are suitable. The administration canalso be done in liquid form, such as, for example, as a juice, to whichoptionally a sweetener is added.

The dosage of the active ingredient can vary depending on method ofadministration, age and weight of the patient, type and severity of thedisease that is to be treated and similar factors. The daily dose is1–2000 mg, preferably 20–500 mg, whereby the dose can be given as anindividual dose to be administered one time or divided into two or moredaily doses.

The NOS-inhibitory action of the compounds of formula I and theirphysiologically compatible salts can be determined according to themethods by Bredt and Snyder in Proc. Natl. Acad. Sci. USA (1989) 86,9030–9033.

The production of the compounds according to the invention is carriedout in that a compound of formula II or its salt

in which

R¹, R², R¹, R¹, R⁶ and X have the above-mentioned meaning, z is oxygenor sulfur and R means C₁₋₆ alkyl, is reacted with ammonia or primaryamines, whereby existing amino groups are optionally intermediatelyprotected and optionally then acylated, the isomers are separated or thesalts are formed.

The reaction with ammonia is possible under pressure in autoclaves withexcess ammonia at low temperatures (−78° C.) or by stirring in methanolthat is saturated with ammonia at room temperature. Thiolactams arepreferably reacted. If the reaction is with amines, first theiminoethers or iminothioethers are produced from lactam or thiolactam asintermediate compounds (e.g., with methyl iodide or methyl sulfate), andthe latter are reacted with or without isolation of the intermediatecompounds with the corresponding amines or their salts.

As amino protective groups, for example, carbamates, such astert-butoxycarbonyl, benzyloxycarbonyl or acetyl, are suitable.

In the precursor stages, optionally sulfides are oxidized, esters aresaponified, acids are esterified, hydroxy groups are etherified oracylated, amines are acylated, alkylated, diazotized, halogenated, NO₂is introduced or reduced, reacted with isocyanates or isothiocyanates,the isomers are separated or the salts are formed.

The saponification of an ester group can be done basically or acidicallyby hydrolysis being performed at room temperature or at an elevatedtemperature up to boiling temperature of the reaction mixture in thepresence of alkali hydroxides in ethanol or other alcohols or with useof acids, such as, e.g., hydrochloric acid, and optionally salts ofaminobenzoxazines or -thiazines being further processed.

The esterification of carboxylic acid is done in a way that is known inthe art with diazomethane or the corresponding alcohol in acid or in thepresence of an activated acid derivative. As activated acid derivatives,for example, acid chloride, acid imidazolide or acid anhydride aresuitable.

The reduction of an ester group to alcohol is carried out in a way thatis known in the art with DIBAH in suitable solvents at low temperatures.The reductive amination of a ketone or a benzaldehyde with amine whileadding boron hydride provides benzylic amines. With suitably selecteddiamines, symmetrical or unsymmetrical amino compounds are obtainedafter identical or different aldehydes are added.

In addition, a nitro group or halogen, especially bromine, can beintroduced by electrophilic, aromatic substitution. Mixtures that areproduced in this case can be separated in the usual way, also usingHPLC. If a nitrile is present, the latter can be saponified according toknown processes or can be converted into the corresponding amine,tetrazole or amidoxime, or it is in a substituted amidine by attackingsubstituted anilines or amines.

The Friedel-Crafts acylation is used successfully in lactams of typeIIa, and then the lactam can be converted selectively into thethiolactam, or the acylation product can be reductively aminated.

The reduction of the nitro group or optionally the cyano group to theamino group is carried out catalytically in polar solvents at roomtemperature or at an elevated temperature under hydrogen pressure. Ascatalysts, metals such as Raney nickel or noble metal catalysts such aspalladium or platinum optionally in the presence of barium sulfate or onvehicles are suitable. Instead of hydrogen, ammonium formate or formicacid can also be used in a known way. Reducing agents such as tin(II)chloride can also be used, such as complex metal hydrides optionally inthe presence of heavy metal salts. The ester group can be advantageouslyintroduced before the reduction as in Formula V. For nitro groups,reduction with zinc or iron in acetic acid has proven its value.

If a single or multiple alkylation of an amino group or a CH-acid carbonposition is desired, alkylation can be performed with, for example,alkyl halides according to commonly used methods. Protection of thelactam group as an anion by a second equivalent base or by a suitableprotective group optionally is necessary.

The acylation of the amino group is carried out in the usual way with,for example, an acid halide or acid anhydride, optionally in thepresence of a base.

The introduction of the halogens chlorine, bromine or iodine via theamino group can also be carried out, for example, according toSandmeyer, by the diazonium salts that are formed intermediately withnitrites being reacted with Cu(I) chloride or Cu(I) bromide in thepresence of the corresponding acids such as hydrochloric acid orhydrobromic acid or being reacted with potassium iodide.

Benzyl alcohols can be converted into corresponding benzyl halides asusual with methanesulfonyl chloride.

The introduction of an NO₂ group is possible by a number of knownnitration methods. For example, nitration can be performed with nitratesor with nitronium tetrafluoroborate in inert solvents, such ashalogenated hydrocarbons or in sulfolane or glacial acetic acid.Introduction by, e.g., nitrating acid in water or concentrated sulfuricacid as a solvent is also possible at temperatures of between −10° C.and 30° C.

The isomer mixtures can be separated into enantiomers or E/Z-isomersaccording to commonly used methods, such as, for example,crystallization, chromatography or salt formation. The enantiomers orenantiomer-pure diastereomers can also be obtained by chromatography onchiral phases as well as by stereoselective syntheses.

The production of the salts is carried out in the usual way, by asolution of the compound of Formula I—optionally also with protectedamino groups—being mixed with the equivalent amount of acid or excessacid, which optionally is in solution, and the precipitate beingseparated or the solution being worked up in the usual way.

Nucleophilic substitution of benzyl halides with secondary amines yieldsthe corresponding benzylamines.

Thiolactams of formula IIa (Z=S) are obtained from, for example, lactamswith phosphorus pentasulfide (P₄S₁₀) or Lawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiaphosphetane-2,4-disulfide) insuitable solvents, and compounds of Formula IIb can be obtained by, forexample, reaction with Meerwein reagent (trimethyloxoniumtetrafluoroborate).

If the production of the starting compounds is not described, the latterare known and commercially available or can be produced analogously toknown compounds or according to processes that are described here.

The production of the compounds of Formula IIa can be carried out, forexample, in that a compound of Formula III

in which R¹ to R³ have the above-mentioned meaning, is reacted with acompound of Formula IV

in which R⁵ and R⁶ have the above-mentioned meaning, and Y is a reactivecarboxyl group such as acid halide, nitrile, carboxylic acid ester, andoptionally is reductively cyclized, or in that a compound of Formula V

is reductively cyclized.

Aromatic thiols of type III are obtained, i.a., as described in Chem.Pharm. Bull. 1991, 39, 2888 and the literature that is mentioned thereby rearrangement of the corresponding dimethylaminothiocarbamates.

The introduction of substituents R¹ to R³ can be carried out in thestage of the compounds of Formula III or II.

For the production of compounds of Formula II, the aldehyde or theketone of the corresponding 1,4-benzoxazine-3-one or1,4-benzothiazine-3(4H)-one can be reductively aminated. This can alsobe done in two places with suitably selected diamines. Diamines can alsobe reacted with the aldehyde of 1,4-benzoxazin-3-one and simultaneouslywith other suitably selected aldehydes. If the introduction of aheteroaryl radical Q is desired, the corresponding halogen derivativecan be substituted nucleophilically with amine. If a primary orsecondary amino group is present, it may be advantageous to protect thelatter intermediately, for example by introduction of atert-butoxycarbonyl group, which is cleaved in the usual way after theamidine formation.

Monoacylated diamines are also obtained, as described in the literature(Synthesis 11; 1988; 917–918), by reaction of benzamides with diaminewith release of ammonia.

New compounds were identified by one or more of the following methods:melting point, mass spectroscopy, NMR. NMR spectra were measured with aBruker 300 MHz device; the (deuterated) solvents are abbreviated asfollows: CDCl₃ (chloroform), DMSO (dimethyl sulfoxide). Alterations areindicated in delta and ppm. Here: m means multiplet, several signals; smeans singlet; d means doublet; dd means double doublet, etc.; tr meanstriplet; q means quartet; H means hydrogen protons; J means couplingconstant. In addition, THF means tetrahydrofuran, DMF meansN,N-dimethylformamide, MeOH means methanol, EE means ethyl acetate, mlmeans milliliter, and RT means room temperature. All solvents are p.A.grade, unless otherwise indicated. All reactions are performed underprotective gas, unless these are aqueous solutions.

Below, the production of several precursors, intermediate products andproducts is described by way of example.

Starting Compounds

A

Mono-N-trifluoroacetyl-1,4-butanediamine

Trifluoroacetamide and 1,4-butanediamine are reacted as described in theliterature (Synthesis 11: 1988; 917–918).

The following, i.a., are produced in the same way:

-   Mono-N-β-chlorobenzoyl-1,4-butanediamine-   mono-N-benzoyl-1,4-butanediamine-   mono-N-trifluoroacetyl-1,5-pentanediamine-   mono-N-β-chlorobenzoyl-1,5-pentanediamine-   mono-N-methanesulfonyl-1,5-pentanediamine

The synthesis of 6-formyl-2-methyl-2H-1,4-benzoxazin-3(4H)-one isdescribed in DE-198 26 232.9, as well as that of6-formyl-2-ethyl-2H-1,4-benzoxazin-3(4H)-one and6-formyl-2-propyl-2H-1,4-benzoxazin-3(4H)-one.

6-{[N-(4-Chlorobenzyl)-pentanecarboxylic acidamide-6-yl]-aminomethyl}-2-methyl-2H-1,4-benzoxazin-3(4H)-one

In 4 ml of methanol, 100 mg of epsilon-amino-pentanecarboxylicacid-para-chlorobenzylamide hydrochloride(ε-aminocaproyl-para-chlorobenzylamide hydrochloride, commerciallyavailable product) is mixed with 0.07 ml of triethylamine. 61 mg of6-formyl-2-methyl-2H-1,4-benzoxazin-3(4H)-one is added to it. It isstirred for 60 minutes at room temperature, and then 16 mg of potassiumborohydride is added. After 2 hours at room temperature, it is pouredinto water, extracted three times with ethyl acetate, and the organicphase is washed with brine. It is dried with magnesium sulfate, and 1.29mg of crude product is concentrated by evaporation.

In the same way, the following are produced from monoacylated diamines:

-   6-{[N-(Trifluoroacetyl)-aminobut-4-yl]-aminomethyl}-2-methyl-2H-1,4-benzoxazin-3(4H)-one-   6-{[N-(4-chlorobenzoyl)-aminobut-4-yl]-aminomethyl}-2-methyl-2H-1,4-benzoxazin-3(4H)-one-   6-{[N-benzoyl-aminobut-4-yl]-aminomethyl}-2-methyl-2H-1,4-benzoxazin-3(4H)-one-   6-{[N-(trifluoroacetyl)-aminopent-5-yl]-aminomethyl}-2-methyl-2H-1,4-benzoxazin-3(4H)-one-   6-{[N-(4-chlorobenzoyl)-aminopent-5-yl]-aminomethyl}-2-methyl-2H-1,4-benzoxazin-3(4H)-one

From 3-(N-pyrrolidin-2-one)-propylamine:

-   6-{[N-(Pyrrolidin-2-one)-prop-3-yl]-aminomethyl}-2-methyl-2H-1,4-benzoxazin-3(4H)-one

From6-keto-6,7,8,9-tetrahydro-2-methyl-2H-naphth[2,3-b]-1,4-oxazin-3(4H)-one

-   6-{[N-(Trifluoroacetyl)-aminobut-4-yl]-amino}-6,7,8,9-tetrahydro-2-methyl-2H-naphth[2,3-b]-1,4-oxazin-3(4H)-one-   6-{[N-methanesulfonylamino-pent-5-yl]-aminomethyl}-2-methyl-2H-1,4-benzoxazin-3(4H)-one    B    N-{[2-Methyl-2H-1,4-benzoxazin-3(4H)-one]-6-yl}-methyl-amino-n-butyl-N′-phenylurea

0.07 ml of triethylamine is added to 80 mg of6-(omega-amino-n-butyl-aminomethyl)-2-methyl-2H-1,4-benzoxazin-3(4H)-onedihydrochloride in 3 ml of THF and 2 ml of DMF, then 27 microliters ofphenylisocyanate is added, and it is stirred for 24 hours at roomtemperature. It is poured into a little water, extracted with ethylacetate, and the organic phase is dried with magnesium sulfate andconcentrated by evaporation. Crude product 95 mg.

The product also containsN-{[2-methyl-2H-1,4-benzoxazin-3(4H)-on]-6-yl}-methyl-(Phenylaminocarbonyl)-amino-n-butyl-N′-phenylurea.

C

6-{[N-(4-Chlorobenzyl)-Pentanecarboxylic acidamide-6-yl]-(tert-butyloxycarbonyl)-aminomethyl}-2-methyl-2H-1,4-benzoxazin-3(4H)-one

129 mg of 6-{[N-(4-chlorobenzyl)-pentanecarboxylic acidamide-6-yl]-aminomethyl}-2-methyl-2H-1,4-benzoxazin-3(4H)-one in 8 ml ofdichloromethane is stirred while 0.127 ml of triethylamine and 163 mg ofdi-tert-butyl dicarbonate are being added. After 12 hours at roomtemperature, it is diluted with dichloromethane, washed with sodiumbicarbonate and then with brine. The organic phase is dried andconcentrated by evaporation. After column chromatography with hexane andethyl acetate, 98 mg of product results.

In the same way, the following are produced:

-   6-{[N-(Trifluoroacetyl)-aminobut-4-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-2-methyl-2H-1,4-benzoxazin-3(4H)-one-   6-{[N-(4-chlorobenzoyl)-aminobut-4-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-2-methyl-2H-1,4-benzoxazin-3(4H)-one-   6-{[N-benzoyl-aminobut-4-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-2-methyl-2H-1,4-benzoxazin-3(4H)-one-   6-{[N-(Trifluoroacetyl)-aminopent-5-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-2-methyl-2H-1,4-benzoxazin-3(4H)-one-   6-{[N-(4-chlorobenzoyl)-aminopent-5-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-2-methyl-2H-1,4-benzoxazin-3(4H)-one-   N-{[2-Methyl-2H-1,4-benzoxazin-3(4H)-one]-6-yl)-methyl-(tert.-butyloxycarbonyl)-amino-n-butyl-N′-phenylurea-   6-{[N-(pyrrolidin-2-one)-prop-3-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-2-methyl-2H-1,4-benzoxazin-3    (4H)-one-   6-{[N-(trifluoroacetyl)-aminobut-4-yl]-(tert.-butyloxycarbonyl)-amino}-6,7,8,9-tetrahydro-2-methyl-2H-naphth[2,3-b]-1,4-oxazin-3(4H)-one-   6-{[N-methanesulfonylamino-pent-5-yl]-(tert.-butyloxycarbonyl)-aminomethyl)-2-methyl-2H-1,4-benzoxazin-3(4H)-one    D    6-{[N-(4-Chlorobenzyl)-pentanecarboxylic    acid-amide-6-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-2-methyl-2H-1,4-benzoxazine-3(4H)-thione

72 mg of Lawesson's reagent is added at room temperature to 95 mg of6-{[N-(4-chlorobenzyl)-pentanecarboxylic acidamide-6-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-2-methyl-2H-1,4-benzoxazin-3(4H)-onein 3 ml of dimethoxyethane, and it is stirred for 8 more hours. Afterconcentration by evaporation and column chromatography with hexane/ethylacetate 2:1, 38 mg of product and 53 mg of6-{[N-(4-chlorobenzyl)-pentanecarboxylic acidthioamide-6-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-2-methyl-2H-1,4-benzoxazine-3(4H)-thioneresult.

In the same way, the following are produced:

-   6-{[N-(Trifluorothioacetyl)-aminobut-4-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-2-methyl-2H-1,4-benzoxazine-3(4H)-thione    and-   6-{[N-(trifluoroacetyl)-aminobut-4-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-2-methyl-2H-1,4-benzoxazine-3(4H)-thione-   6-{[N-(4-Chlorobenzoyl)-aminobut-4-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-2-methyl-2H-1,4-benzoxazine-3(4H)-thione    and-   6-{[N-(4-chlorothiobenzoyl)-aminobut-4-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-2-methyl-2H-1,4-benzoxazine-3(4H)-thione-   6-{[N-Thiobenzoyl-aminobut-4-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-2-methyl-2H-1,4-benzoxazine-3(4H)-thione-   6-{[N-(Trifluorothioacetyl)-aminopent-5-yl]-(tert.-butyloxycarbonyl-aminomethyl}-2-methyl-2H-1,4-benzoxazine-3(4H)-thione-   6-{[N-(thio-4-chlorobenzoyl)-aminopent-5-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-2-methyl-2H-1,4-benzoxazine-3(4H)-thione-   N-{[2-Methyl-2H-1,4-benzoxazine-3(4H)-thione]-6-yl)-methyl-(tert.-butyloxycarbonyl)-amino-n-butyl-N′-phenylurea-   6-{[N-(Pyrrolidine-2-thione)-prop-3-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-2-methyl-2H-1,4-benzoxazine-3(4H)-thione-   6-{[N-(Trifluorothioacetyl)-aminobut-4-yl]-(tert.butyloxycarbonyl)-amino}-6,7,8,9-tetrahydro-2-methyl-2H-naphth[2,3-b]-1,4-oxazine-3(4H)-thione    and-   6-{[N-(trifluoroacetyl)-aminobut-4-yl]-(tert.-butyloxycarbonyl)-amino}-6.7,8,9-tetrahydro-2-methyl-2H-naphth-2,3-b]-1,4-oxazine-3(4H)-thione-   6-{[N-Methanesulfonylamino-pent-5-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-2-methyl-2H-1,4-benzoxazine-3(4H)-thione

EXAMPLE 1 6-{[N-(4-Chlorobenzyl)-pentanecarboxylic acidthioamide-6-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine

50 mg of 6-([N-(4-chlorobenzyl)-pentanecarboxylic acidthioamide-6-yl]-(tert.-butyloxycarbonyl)-aminomethyl)-2-methyl-2H-1,4-benzoxazine-3(4H)-thionein 50 ml of saturated ammonia solution is stirred in methanol(commercially available). After one day at room temperature, the crudeproduct is obtained after concentration by evaporation. Columnchromatography with ethyl acetate purifies the product. A 92% yieldresults.

MS (ei): 544 (7%), 545 (3%), 546 (4%) m/z.

In the same way, the following are produced:

-   6-{[N-(Trifluoroacetyl)-aminobut-4-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine-   6-{[N-trifluorothioacetyl)-aminobut-4-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine-   6-{[N-(4-Chlorobenzoyl)-aminobut-4-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine-   6-{[N-(4-chlorothiobenzoyl)-aminobut-4-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine-   6-{[N-benzoyl-aminobut-4-yl]1-(tert.-butyloxycarbonyl)-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine-   6-{[N-(trifluoroacetyl)-aminopent-5-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine-   6-{[N-(4-chlorobenzoyl)-aminopent-5-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine-   N-[(3-amino-2-methyl-2H-1,4-benzoxazine-6-yl)-methyl-(tert-butyloxycarbonyl)-amino]-n-butyl-N′-phenylurea-   6-{[N-(pyrrolidine-2-thione)-prop-3-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine

MS (ei): 432 (27%), 433 (6%) m/z

-   6-{[N-(Trifluoroacetyl)-aminobut-4-yl]-(tert.-butyloxycarbonyl)-amino}-6,7,8,9-tetrahydro-3-amino-2-methyl-2H-naphth[2,3-b]-1,4-oxazine-   6-{[N-Methanesulfonylamino-pent-5-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine

MS (ei): 454 (6%), 455 (2%) m/z

EXAMPLE 2 6-{[N-(4-Chlorobenzyl)-pentanecarboxylic acidthioamide-6-yl]-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazinedihydrochloride

45 mg of 6-{[N-(4-chlorobenzyl)-pentanecarboxylic acidthioamide-6-yl]-(tert.-butyloxycarbonyl)-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazineis stirred in 1 ml of THF with 1 ml of 4N hydrochloric acid (solution indioxane). After 12 hours, it is evaporated to the dry state. 32 mg ofproduct (76% yield) is obtained.

[1H]-NMR (MeOH): 7.28 1H, 7.22 4H, 7.21 1H, 7.05 d 1H, 5.16 q 1H, 4.72H, 4.1 s broad 2H, 2.93 m 2H, 2.58 tr 2H, 1.7 m 4H, 1.48 d 3H, 1.33 m2H.

In the same way, the following are produced:

-   6-{[N-(Trifluoroacetyl)-aminobut-4-yl]-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine    dihydrochloride

[1H]-NMR (DMSO): 9.5 s broad 1H and 9.2 s broad 1H, 7.42 d 1H J=1Hz,7.33 dd 1H, 7.11 d J=8 Hz 1H, 5.32 q 1H, 4.09 s broad 2H, 3.2 m 2H, 2.9m 2H, 1.65 m 2H and 1.55 m 2H, 1.49 d 3H.

-   6-{[N-(Trifluorothioacetyl)-aminobut-4-yl]-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine    dihydrochloride-   6-{[N-(4-chlorobenzoyl)-aminobut-4-yl]-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine    dihydrochloride

[1H]-NMR (DMSO): 9.5 s broad 1H, 9.3 s broad 1H and 8.6 s broad 1H, 7.9d 2H, 7.53 d 2H, 7.45 d 1H, J=1Hz, 7.32 dd 1H, 7.11 d 1H, 5.35 q 1H, 4.1s broad 2H, 3.3 m 2H, 2.9 m 2H, 1.7 m 2H and 1.6 m 2H, 1.49 d 3H. MS(ei): 400, 401 m/z (visible as a free base).

-   6-{[N-(4-Chlorothiobenzoyl)-aminobut-4-yl]-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine    dihydrochloride-   6-{[N-benzoyl-aminobut-4-yl]-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine    dihydrochloride-   6-{[N-(trifluoroacetyl)-aminopent-5-yl]-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine    dihydrochloride-   6-{[N-(4-chlorobenzoyl)-aminopent-5-yl]-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine    dihydrochloride-   N-{[3-amino-2-methyl-2H-1,4-benzoxazine-6-yl]-methylamino)-n-butyl-N′-phenylurea    dihydrochloride-   6-{[N-(pyrrolidine-2-thione)-prop-3-yl]-aminomethyl}-3-amino-2-methyl-2H-1,    4-benzoxazine dihydrochloride

[1H]-NMR (DMSO): 9.7 broad 1H, 9.5 broad 1H and 9.3 broad 1H, 7.45 d 1H,7.33 dd 1H, 7.13 d 1H, 5.35 q 1H, 4.11 s broad 2H, 3.7 m 4H, 3.4 m 2H,2.9 m 2H, 2.0 m 4H, 1.51 d 3H.

-   6-{[N-(Trifluoroacetyl)-aminobut-4-yl]-amino}-6,7,8,9-tetrahydro-3-amino-2-methyl-2H-naphth[2,3-b]-1,4-oxazine    dihydrochloride

[1H]-NMR(MeOH); 7.29 s 1H, 6.85 s 1H, 5.13 q 1H, 4.4 m 1H in 6-position,3.22 m 2H, 3.08 tr 2H, 2.8 m 2H, 2.7 m 2H, 2.15 m 1H, 2.0 m 1H, 1.75 m2H, 1.6 m 2H, 1.45 m 2H, 1.47 d 3H, MS (ei): 397 (11%), 398 (4%) m/z(fragment of free base).

-   6-{[N-Methanesulfonylamino-pent-5-yl]-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine    dihydrochloride

[1H]-NMR(MeOH): 7.31 d 1H J=1Hz, 7.23 dd 1H, 7.05 d 1H, 5.18 q 1H, 4.10s broad 2H, 3.5 m 2H, 2.99 m 4H, 2.82 s 3H methyl, 1.8 to 1.4 m 4H, 1.48d 3H.

MS (ei): 353 (2%), 354 (2%) m/z (fragment of free base).

1. A compound of the formula I, a tautomeric or isomeric form thereof or a salt thereof:

in which X means O; R¹ means —(CHR⁹)_(n)—NR⁷—A—NR⁸—B, —(CHR⁹)_(n)—NR⁷—(CH₂)_(p)—CR—(CH₂)_(q)—NR⁸—D, or —(CHR⁹)_(n)—NR⁷—B; R² means hydrogen; or R¹ and R² together with two adjacent carbon atoms form a 5-, 6-, 7- or 8-membered ring, which is monocyclic or bicyclic, saturated or unsaturated and in which 1 or 2 CH₂ groups are optionally replaced by oxygen or carbonyl, and which is substituted with —(CHR⁹)_(r)—NR⁷—A—NR⁸—B, —(CHR⁹)_(r)—NR⁷—(CH₂)_(p)—CR—(CH₂)_(q)—NR⁸—D, or —(CHR⁹)_(r)—NR⁷—B and is optionally substituted with C₁₋₄alkyl; R³ means hydrogen, halogen, NO₂, cyano, CF₃, —OCF₃, —S—R⁹, —O—R⁹, C₃₋₇cycloalkyl, —NR⁹—C(═NR¹⁰)—R¹¹, —NH—CS—NR¹²R¹³, —NH—CO—NR¹²R¹³, —SO₂NR¹²R¹³, —CO—NR¹²R¹³, —CO—R¹⁴, —NR¹⁵R¹⁶, C₆₋₁₀aryl which optionally is substituted with halogen, cyano, C₁₋₄alkyl, —S—R⁹ or —O—R⁹; or 5- or 6-membered heteroaryl with 1 to 4 oxygen, sulfur or nitrogen atoms: or C₁₋₆alkyl, which optionally is substituted with halogen, —OR9, —SR⁹, —NR¹²R¹³, ═NR¹², ═NOC₁₋₅alkyl, ═N—NH-aryl, phenyl, C₃₋₇cycloalkyl or 5- or 6-membered heteroaryl; or C₂₋₅alkenyl, which optionally is substituted with halogen, CONH₂, CN or phenyl; or C₂₋₆alkynyl, which optionally is substituted with halogen, CONH₂, CN or phenyl; R⁴ means hydrogen or acyl; R⁵ and R⁶, independently of one another, mean hydrogen, C₃₋₇cycloalkyl, phenyl, C₁₋₆alkyl, C₂₋₆alkenyl or C₂₋₆alkynyl radicals, which are optionally substituted in each case with halogen, OH, O—C₁₋₆alkyl, SH, S—C₁₋₆alkyl, NR¹⁵R¹⁶, 5- or 6-membered heteroaryl with 1–3 N, O or S atoms, phenyl or C₃₋₇cycloalkyl; R⁷ means hydrogen or C₁₋₆alkyl, which is optionally substituted with phenyl, COOC₁₋₆alkyl or COC₁₋₆alkyl; R⁸ means hydrogen; A means straight-chain or branched C₁₋₄alkylene, straight-chain or branched C₂₋₆alkenylene or —(CH₂)_(p)—Q—(CH₂)_(q)—; B means —CR—(CH₂)_(p)—U, —CR—NR¹⁵R¹⁶, —SOR¹², —SO₂R¹², —COO-aryl, or —COO-benzyl; D means hydrogen or —(CH₂)_(p)—U; R means oxygen or sulfur; Q means C₃₋₇cycloalkylene, indanylene, 5-, 6- or 7-membered saturated heterocyclo-alkylene with 1–2 N, O or S atoms in the heterocyclo ring, C₆–C₁₀ arylene, or 5- or 6-membered heteroarylene with 1–3 N, O or S atoms which is optionally annellated with benzene; U means hydrogen, C₁₋₆alkyl optionally substituted with halogen, C₃₋₇cycloalkyl, indanyl, C₇₋₁₀bicycloalkyl, C₆₋₁₀aryl or 5- or 6-membered heteroaryl with 1–3 N, O or S atoms which is optionally annellated with benzene, whereby the aryl and heteroaryl radical are optionally substituted with halogen, C₁₋₄alkyl, C₁₋₄alkoxy, CF₃, NO₂, NH₂, —N(C₁₋₄ alkyl)₂, cyano, —CONH₂, —O—CH₂—O—, —O—(CH₂)₂—O—, SO₂NH₂, OH, phenoxy or —COOC₁₋₄alkyl; or R⁸ and B together with the nitrogen atom to which they are bonded form a 5- to 7-membered saturated heterocyclic group, which contains an oxo or thioxo group on the ring and optionally contains another oxygen, nitrogen or sulfur atom and is optionally substituted with C₁₋₄alkyl or a phenyl, benzyl or benzoyl radical that is optionally substituted with halogen; or R⁷ and A together with the nitrogen atom to which they are bonded form a 5- to 7-membered saturated heterocyclic group, or form an unsaturated 5-membered heterocyclic group; m means 0, 1 or 2; n and r independently of each other mean 0 to 6; p and q independently of each other mean 0 to 6; R⁹ and R¹⁰ independently of each other mean hydrogen or C₁₋₆alkyl; R¹¹ means C₁₋₆alkyl, —NH₂, —NH—CH₃, —NH—CN, C₆₋₁₀aryl optionally substituted with halogen, C₁₋₄alkyl or CF₃, or 5- or 6-membered heteroaryl with 1 to 4 nitrogen, sulfur or oxygen atoms that is optionally substituted with halogen, C₁₋₄alkyl or CF₃; R¹² and R¹³ independently of each other mean hydrogen, C₁₋₄ alkyl, phenyl optionally substituted with halogen or C₁₋₄ alkyl, benzyl optionally substituted with halogen or C₁₋₄alkyl, or C₃₋₇cycloalkyl; R¹⁴ means hydrogen, hydroxy, C₁₋₆alkoxy, phenyl, C₁₋₄alkyl (optionally substituted with CO₂H, CO₂C₁₋₆alkyl, hydroxy, C₁₋₄alkoxy, halogen, NR¹⁵R¹⁶, CONR¹²R¹³, or phenyl), or C₂₋₆ alkenyl (optionally substituted with phenyl, cyano, CONR¹²R¹³ or CO₂C₁₋₄ alkyl); R¹⁵ and R¹⁶ independently of each other mean hydrogen, C₁₋₆alkyl, phenyl optionally substituted with halogen or C₁₋₄ alkyl, or benzyl optionally substituted with halogen or C₁₋₄alkyl; or R¹⁵ and R¹⁶ together with the nitrogen atom to which they are bonded form a saturated 5-, 6-, or 7-membered ring, which optionally contains a nitrogen, oxygen or sulfur atom and is optionally substituted with C₁₋₄alkyl, or a phenyl, benzyl or benzoyl radical optionally substituted with halogen.
 2. A compound of claim 1, in which R⁶ is hydrogen.
 3. A compound of claim 1, in which R⁵ is C₁₋₆alkyl.
 4. A compound of claim 1, in which R⁴ is hydrogen.
 5. A compound of claim 1, in which R³ is hydrogen.
 6. A compound of claim 1, in which A is a straight-chain or branched C₁₋₆alkylene.
 7. A compound of claim 1, which is: 6-{[N-(trifluoroacetyl)-aminobut-4-yl]-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine dihydrochloride; 6-{[N-trifluorothioacetyl)-aminobut-4-yl]aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine dihydrochloride; 6-{[N-(4-chlorobenzoyl)-aminobut-4-yl]aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine dihydrochloride; 6-{[N-(4-chlorothiobenzoyl)-aminobut-4-yl]-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine dihydrochloride; 6-{[N-benzoyl-aminobut-4-yl]aminomethyl}3-amino-2-methyl-2H-1,4-benzoxazine dihydrochloride; 6-{[N-(trifluoroacetyl-aminopent-5-yl]-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine dihydrochloride; 6-{[N-(4-chlorobenzoyl)-aminopent-5-yl]-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine dihydrochloride; N-{[3-amino-2-methyl-2H-1,4-benzoxazine-6-yl]-methylamino}-n-butyl-N′-phenylurea dihydrochloride; 6-{[N-(pyrrolidine-2-thione)-prop-3-yl]-aminomethyl}-3-amino-2-methyl-2H-1,4-benzoxazine dihydrochloride; 6-{[N-(trifluoroacetyl)-aminobut-4-yl]-amino}-6,7,8,9-tetrahydro-3-amino-2-methyl-2H-naphth[2,3-b]-1,4-oxazine dihydrochloride; or 6{[N-methanesulfonylamino-pent-5-yl]-aminomethyl}amino-2-methyl-2H-1,4-benzoxazine dihydrochloride.
 8. A pharmaceutical composition which comprises a compound according to claim 1 and one or more pharmaceutically common vehicles or adjuvants.
 9. A compound of claim 1, wherein: aryl is naphthyl or phenyl, each of which is optionally substituted in one to three places; heteroaryl is imidazole, indole, isooxazole, isothiazole, furan, oxadiazole, oxazole, pyrazine, pyridazine, pyrimidine, pyridine, pyrazole, pyrrole, tetrazole, thiazole, triazole, thiophene, thiadiazole, benzimidazole, benzofuran, benzoxazole, isoquinoline, or quinoline, each of which is optionally substituted in one to three places; saturated heterocyclic group is piperidine, pyrrolidine, morpholine, thiomorpholine, hexahydroazepine or piperazine, each of which is optionally substituted in one to three places; when —NR⁷A— together with the nitrogen atom forms an unsaturated heterocyclic group, it is imidazole, pyrrole, pyrazole or triazole; and acyl is the acyl residue from a straight-chain or branched aliphatic C₁₋₆carboxylic acid, a benzenesulfonic acid which is optionally substituted with halogen or C₁₋₄alkyl, or a C₁₋₄ alkanesulfonic acid.
 10. A compound of claim 1, wherein R³, R⁴, R⁷ and R⁹ are each hydrogen.
 11. A compound of claim 1 wherein R¹ is at the 6-position of the benzoxazine ring.
 12. A compound of claim 1, wherein R⁸ and B together with the nitrogen atom to which they are bonded form a pyrrolidine-2-thione group.
 13. A compound of claim 1, wherein R¹ is —(CHR⁹)_(n)—NR⁷—A—NR⁸—B or —(CHR⁹)_(n)—NR⁷—B; or R¹ and R² together form a 5-, 6-, 7- or 8-membered ring which is substituted by —(CHR⁹)_(n)—NR⁷—A—NR⁵—B, or —(CHR⁹)_(n)—NR⁷—B; and B is: —CR—(CH₂)_(p)—U wherein —(CH₂)_(p)—U is hydrogen, C₁₋₆alkyl optionally substituted with halogen, or phenyl optionally substituted with halogen, C₁₋₄alkyl, C₁₋₄alkoxy or CF₃; or —CR—NR¹⁵R¹⁶ wherein R¹⁵ and R¹⁶ are each hydrogen, C₁₋₆ alkyl or phenyl; or —SO₂R¹² in which R¹² is C₁₋₆alkyl.
 14. A compound of claim 1, wherein R¹ is —(CHR⁹)_(r)—NR⁷—(CH₂)_(p)—CR—(CH₂)_(q)—NR⁶—D, or R¹ and R² together form a 5-, 6-, 7- or 8-membered ring which is substituted by —(CHR⁹)_(r)—NR⁷—(CH₂)_(p)—CR—(CH₂)_(q)—NR⁸—D, and D is hydrogen or a benzyl radical that is optionally substituted with halogen, C₁₋₄alkoxy, CF₃ or C₁₋₄alkyl.
 15. A compound of claim 1, wherein R¹ is —(CHR⁹)_(r)—NR⁷—(CH₂)_(p)—CR—(CH₂)_(q) —NR⁸—D, or R¹ and R² together form a 5-, 6-, 7- or 8-membered ring which is substituted by —(CHR⁹)_(r)—NR⁷—(CH₂)_(p)—CR—(CH₂)_(q)—NR⁸—D, and at least one of (CH₂)_(p) and (CH₂)_(q) is alkylene of 1–6 carbon atoms.
 16. A compound of claim 1, wherein R³ is —NR⁹—C(═NR¹⁰)—R¹¹, where R¹¹ is thienyl. 